The overall goal of this research program is to understand the role of the c-Jun N-terminal kinase (JNK) group of mitogen-activated protein kinases in leukemia. The JNK signaling pathway is activated in cells transformed by the leukemogenic oncogene Bcr/Abl. Targets of the JNK pathway include transcription factors (e.g. AP- 1, Ets, and NFAT). Phosphorylation of these transcription factors by JNK regulates gene expression. This process is implicated in leukemogenic transformation by Bcr/Abl. I propose to examine the role of the JNK signaling pathway in leukemogenesis in vitro and in vivo. During the previous research period, we have constructed mice with targeted disruptions of components of the JNK pathway, including all three Jnk genes and both of the genes that encode the protein kinases that activate JNK. Compound mutant mice v'ith disruptions in these genes have also been obtained. These mice will be used to test the role of JNK Jn ieukemogenesis and to examine the molecular mechanisms that account for the actions of JNK in leukemic cells. Achievement of the goals of this proposal will increase understanding of signal transduction mechanisms that contribute to leukemogenesis. This information may represent a basis lbr the design of novel therapeutic strategies. The Specific Aims of this proposal are to: 1. Define the role of JNK in Bcr/Abl-induced leukemia. 2. Define the role of JNK in leukemic cell survival.